F-18去氧葡萄糖正子造影運用於鼻咽癌之效用及經濟評估

Abstract

目的: 鼻咽癌為一種盛行於台灣地區之頭頸部癌症。對於局部鼻咽癌患者，其治療方式為合併放化療或誘導性化療後再施與合併化放療。在使用誘導性化療患者，如果我們能在施予誘導性化療初期，即早評估誘導性化療的效益，可儘速調整該鼻咽癌患者之治療策略，以避免無效化療的副作用。此外鼻咽癌患者之長期存活率主要取決於局部復發或遠端轉移之早期偵測。在合併放化療完成後，局部及周圍組織會發生壞死和纖維化，使傳統的CT/MRI解剖影像檢查往往很難偵測復發病灶。近年來，F-18去氧葡萄糖 (18F-FDG) 正子造影 (PET) 之體內葡萄糖的代謝影像，利用惡性腫瘤組織較正常組織容易攝取18F-FDG之特性，在其他腫瘤被認為可即早偵測療效，並可偵測早期復發/轉移之病灶。18F-FDG PET使用於鼻咽癌療效評估及早期復發/轉移病灶之偵測尚未被透徹的研究過。本研究主要目的為探討18F-FDG PET使用於: (1) 誘導性化療在局部鼻咽癌患者之早期療效及預後之評估， (2) 早期偵測鼻咽癌復發/轉移病灶之效益。最後， (3) 以決策分析樹狀圖來評估高價位正子掃描對早期偵測鼻咽癌局部復發是否符合經濟效益。 方法: 本研究分為三部份。第一部份為50 位接受誘導性化療之局部鼻咽癌患者，在誘導性化療之第一 (33位) 或第二 (17位) 療程後使用18F-FDG PET 來評估誘導性化療療效，用患者18F-FDG PET的結果做再分期，如果患者PET分期下降為stage I或 stage II，將之歸為有療效反應組，如果患者PET分期仍為stage III或 stage IV，將之歸為無顯著療效反應組。並將PET分期結果和這些患者的後續追蹤結果做相關性分析。第二部份為64 位接受合併放化療或誘導性化療後的鼻咽癌患者，評估18F-FDG PET用來偵測復發或轉移病灶的效益，並以18F-FDG PET結果和患者預後做存活分析。第三部份則以決策分析樹狀圖針對三種偵測鼻咽癌復發之方案: 只使用MRI、只使用PET和MRI-PET(若MRI結果不確定則加做PET)做成本效益分析。 結果: 本研究顯示18F-FDG PET 在 (1) 評估診斷誘導性化療療效使用上，23個有療效反應者只有一位後來產生局部復發，相反的27個無顯著療效反應有15位後來產生局部復發或遠端轉移。存活分析也顯示有療效反應組其存活時間比無顯著療效組長且具有顯著統計意義。(2) 鼻咽癌復發或轉移病灶的偵測有很高的精確度 (92%)， 而且正子造影結果有無18F-FDG 的異常代謝之病灶和其存活時間有高相關性。(3) 使用樹狀圖分析用三種方案偵測鼻咽癌復發之品質校正存活人命分別為16.16 QALYs (MRI方案)、 16.70 QALYs (PET方案)、17.35 QALYs (MRI-PET方案). MRI-PET方案相對於MRI方案 每增加一個QALYs 需多花費US$462 (US$550/1.19)。 MRI-PET方案對PET方案擁有壓倒性優勢，因為MRI-PET方案花費較低而所得QALYs 較高。 結論: 本研究顯示18F-FDG PET (1)在誘導性化療第一或第二療程後之再分期可正確預測誘導性化療之療效及鼻咽癌患者之預後。 (2) 對接受化放療後之鼻咽癌患者，可早期偵測復發及轉移病灶。而且也是一個有效的預後指標。(3) 對於早期偵測復發鼻咽癌病灶，以現在的成本結構計算， MRI-PET 方案最具成本效益，但如果PET費用如能較MRI費用降低更快，在不久的未來PET方案應可成為最有成本效益的方案。

Objective: Nasopharyngeal carcinoma (NPC) is a head and neck malignancy prevalent in Taiwan. For NPC patients with locoregionally advanced disease, induction chemotherapy (IC) followed by concurrent chemoradiotherapy has been the preferred therapeutic approach for improving locoregional control and eradicating micrometastases. It is of great advantage if we are capable of identifying the non-responders during or immediately after induction therapy such that alternative treatment strategies may be formulated as early as possible. Besides, the loco-regional recurrences and distant metastases are crucial prognostic factors for NPC patients after their treatments. Nonetheless, conventional MRI and CT have relatively low sensitivity and moderate specificity in distinguishing residual/recurrent lesions from post-therapy changes because a variety of changes in the nasopharyngeal tissue caused by radiotherapy may obscure the detection of tumor recurrence by these anatomical imaging studies. It has been reported that positron emission tomography (PET) using 18-fluoro-2-deoxyglucose (18F-FDG), based on the property that 18F-FDG is prone to accumulate in the malignancy, is a promising tool for evaluating therapeutic responses of several malignancies and for distinguishing recurrent tumors from post-treatment changes in the nasopharynx. To the best of my knowledge, the usages of 18F-FDG PET for NPC patients in these two categories have not been fully evaluated yet. This study of mine is to evaluate the usefulness of 18F-FDG PET for the therapeutic responses during and after induction therapy and the usefulness of 18F-FDG PET for the early detection of recurrence/metastases in the follow-up of NPC patients, and to perform a cost-effectiveness analysis to determine the optimized usage for the follow-up of NPC patients by 18F-FDG PET which is known to be prohibitively expensive. Study Design: This study includes 3 parts: The first part studies therapeutic responses of NPC patients by PET. 50 patients (19 female and 31 male with age 17-72 years; mean, 45.9 ± 11.9) who had histologically proven locoregionally advanced NPC without distant metastasis and had received IC were recruited in this part of study. Whole-body 18F-FDG PET was performed for each patient after completion of one (33 patients) or two (17 patients) courses of IC. Each patient was restaged by 18F-FDG PET results. Patients who were downstaged to stage I or II were classified as major-responders. The rest were classified as non-major-responders. The PET restaging results were correlated with follow-up results of these patients. The second part studies 64 Taiwanese NPC patients, 14 female and 50 male (age range, 16-75 years; mean age, 45.8±13.0 years) who received 18F-FDG PET studies at 4-70 months (mean: 14.1± 13.5 months) after radiotherapy or induction chemotherapy followed by concurrent chemoradiotherapy. The second part of study evaluates the effectiveness and prognostic significance of whole-body 18F-FDG PET in the diagnosis of recurrent/metastatic NPC and in the follow-up examination of these NPC patients. For the third part, an analysis for cost-effectiveness is performed based on the decision-tree model for three different strategies: (1) MRI-only, (2) PET-only, and (3) MRI-PET (performing PET scan if MRI result is uncertain) to analyze the cost-effectiveness of 18F-FDG PET for detecting loco-regional recurrences for NPC patients after RT or CCRT therapy. Results: (Part 1) Only 1 of the 23 major-responders developed local recurrence afterwards. They were all alive at the time of data analysis. On the other hand, 15 of the 27 non-major-responders had locoregional recurrence or distant metastasis. Among these non-major-responders, 7 died of NPC and 2 died of therapeutic complications at the time of data analysis. Kaplan-Meier survival analysis showed significantly longer recurrence-free survival and overall survival in major-responders (56.4 ±9.2 and 58.1±2.2 months) as compared to non-major-responders (33.7 ±23.2 and 44.7±20.0 months) with p < 0.0001 and p = 0.0024, respectively. (Part 2) The sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of 18F-FDG PET images in the diagnosis of NPC recurrence/ metastases and secondary primary cancers were 92%, 90%, 92%, 90% and 91%, respectively. Furthermore, the presence of 18F-FDG hypermetabolism was found to be highly correlated with the survival time of NPC patients. (Part 3) Plugging the data for utilities and life expectancies in the decision tree model, the quality adjusted life expectancies are found to be 16.16 QALYs for strategy 1, 16.70 QALYs for strategy 2 and 17.35 QALYs for strategy 3. The additional cost per additional QALYs for strategy 3 relative to strategy 1 is calculated to be US$62 (US$550/1.19). Strategy 3 dominates over strategy 2 because strategy 3 costs less and yields more QALYs than strategy 2. Conclusion: The results suggest that (Part 1) early restaging by whole-body 18F-FDG PET performed after the 1st or the 2nd course of IC is useful for predicting therapeutic response and outcome for locoregionally advanced NPC patients; (Part 2) whole-body 18F-FDG PET is a sensitive follow-up diagnostic tool for the evaluation of NPC recurrences and metastases. It is also an effective prognostic indicator for NPC patients. Finally, (Part 3) the decision tree analysis shows that MRI-PET strategy is the most cost-effective for now. In the near future, as the cost of PET scan decreases in a faster rate than the cost of MRI does, it is likely the PET-only strategy will become the most cost-effective strategy for recurrent NPC patients.